Dataset Information

ECM composition dictates the mode of cell competition and competence for tumor initiation

ABSTRACT: The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. Basal cell carcinoma (BCC) is the most frequent cancer in human4,5. Cell competition, the elimination of less fit cells by their neighboring winners, has been proposed to be important for tumour initiation6-10. Recent studies identified somatic mutations in cancer drivers in normal tissues lead to clonal expansion of these mutated cells11-16. However, the ways in which oncogenic mutations impact the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development is currently unknown. Using multidisciplinary approaches which combine lineage tracing, clonal analysis in living animals, single cell sequencing, quantitative proteomics, and functional experiments, we have investigated the mode of cell competition and the ability of oncogene-expressing cells to develop invasive BCC in different skin regions. The quantitative proteomics analysis of the ear and backskin dermis before and 6 weeks after oncogene expression was performed to investigate whether a different composition of the dermis in the ear and the backskin affects the ability of oncogene targeted cells to form BCC. To investigate whether a different composition of the dermis in the ear and the backskin affects the ability of oncogene targeted cells to form BCC, we performed an unbiased quantitative proteomics analysis of the ear and backskin dermis before and 6 weeks after oncogene expression. This analysis revealed that only very few proteins were more highly expressed in the backskin as compared to the ear and included Col1a1 and Col1a2 in WT conditions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Dermis, Skin

SUBMITTER: Evy Timmerman

LAB HEAD: Cédric Blanpain

PROVIDER: PXD041644 | Pride | 2023-11-27

REPOSITORIES: Pride

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			Action	DRS
	F007596_2p_110uPACG2v2_3_trapPM7_PRC-5883_1.raw	Raw
	F007598_2p_110uPACG2v2_3_trapPM7_PRC-5883_2.raw	Raw
	F007600_2p_110uPACG2v2_3_trapPM7_PRC-5883_3.raw	Raw
	F007602_2p_110uPACG2v2_3_trapPM7_PRC-5883_4.raw	Raw
	F007604_2p_110uPACG2v2_3_trapPM7_PRC-5883_5.raw	Raw

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Publications

The extracellular matrix dictates regional competence for tumour initiation.

Bansaccal Nordin N Vieugue Pauline P Sarate Rahul R Song Yura Y Minguijon Esmeralda E Miroshnikova Yekaterina A YA Zeuschner Dagmar D Collin Amandine A Allard Justine J Engelman Dan D Delaunois Anne-Lise AL Liagre Mélanie M de Groote Leona L Timmerman Evy E Van Haver Delphi D Impens Francis F Salmon Isabelle I Wickström Sara A SA Sifrim Alejandro A Blanpain Cédric C

Nature 20231115 7988

The skin epidermis is constantly renewed throughout life<sup>1,2</sup>. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation<sup>3</sup>. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravi ...[more]

PMID: 37968399

Similar Datasets

Project description:The skin epidermis is constantly renewed throughout life. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumor initiation. Basal cell carcinoma (BCC) is the most frequent cancer in human. Cell competition is a biological process that leads to the elimination of cells by winner cells, which have been proposed to be important for tumour initiation. Recent studies identified somatic mutations in cancer drivers in normal tissues that get colonized by clones carrying oncogenic mutations. However, how the different oncogenic mutations impact the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumor development is currently unknown. Here, using multidisciplinary approaches combining in vivo clonal analysis using intra-vital microscopy, single cell analysis, and functional analysis, we defined at a single cell resolution in living animals how mutations associated with BCC development (SmoM2) affect clonal competition and tumor initiation in real time. We found that SmoM2 expression in the ear epidermis induces a stereotypical pattern of cell competition with clonal expansion leading tumor initiation and invasion. In contrast, SmoM2 expression in the back skin epidermis led to a similar clonal expansion that induces lateral cell competition but without inducing dermal invasion and tumor formation. Single cell analysis showed that oncogene expression is associated with a cellular reprogramming of adult interfollicular cells into embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparison between ear and back skin epidermis revealed a very different composition of the dermis with increased stiffness and a denser collagen 1 network in the back skin. Decreasing Collagen 1 expression in the back skin overcame the natural resistance of these cells to undergo EHFP reprogramming and tumor initiation following SmoM2 expression. Altogether our study demonstrates that ECM composition controls the mode of clonal competition and competence to undergo oncogenic transformation upon oncogene expression.

Project description:Sulfur mustard (SM) is a potent alkylating agent. We are developing medical countermeasures to reduce the injury caused by SM exposure. Screening in the mouse ear vesicant model has identified three effective compounds: dimercaprol (British anti-lewisite), indomethacin, and octyl homovanillamide (OHV). To identify gene expression changes that correlate with compound efficacy we used oligonucleotide microarrays to compare gene expression profiles in vehicle-exposed skin, SM-exposed skin, and skin pretreated with each compound before SM exposure. Mice were topically exposed on the inner surface of the right ear to SM alone or pretreated for 15 min with one of the compounds and then exposed to SM. Left ears were vehicle-exposed. Ear tissue was harvested 24 hr later for ear weight determination (an endpoint indicating compound efficacy). The exposure groups were: methylene chloride (sulfur mustard vehicle); ethanol (drug vehicle); 0.08 mg sulfur mustard; 6.25 mg dimercaprol 15 min before 0.08 mg sulfur mustard; 1.34 mg indomethacin 15 min before 0.08 mg sulfur mustard; 0.6 mg octylhomovanillamide 15 min before 0.08 mg sulfur mustard; 6.25 mg dimercaprol alone; 1.34 mg indomethacin alone; 0.6 mg octylhomovanillamide alone. RNA was extracted from the tissues and used to generate oligonucleotide microarray probes. Principal component analysis of the gene expression data revealed partitioning of the samples based on drug treatment and SM exposure. Vehicle-exposed mouse ears clustered away from the other treatment groups. SM-exposed mouse ears pretreated with dimercaprol or OHV clustered more closely with vehicle-exposed ears, while SM-exposed mouse ears pretreated with indomethacin clustered more closely with SM-exposed ears. This clustering of the samples is supported by the ear weight data, in which the indomethacin group has ear weights closer to the SM-exposed group, whereas the dimercaprol and OHV groups have ear weights closer to the vehicle-exposed group. Correlation coefficients were calculated for each gene based on the correlation between gene expression level and ear weight. These data provide the basis for understanding what gene expression changes are important in the development of effective SM medical countermeasures. Experiment Overall Design: Exposure of mouse ears to sulfur mustard alone, sulfur mustard preceded by drug treatment, or vehicle compounds. Naive controls were also included. Biological replicates of at least n=3 were examined for each exposure condition.